Eur J Haematol 2004: 72: 79–88 Copyright
Blackwell Munksgaard 2004

Printed in UK. All rights reserved

EUROPEAN
JOURNAL OF HAEMATOLOGY

Review article

Monoclonal antibodies in the treatment

of autoimmune cytopenias
Robak T. Monoclonal antibodies in the treatment of autoimmune Tadeusz Robak
cytopenias. Department of Hematology, Medical University of
Eur J Haematol 2004: 72: 79–88.
Blackwell Munksgaard 2004. Lodz and Copernicus Hospital, Lodz, Poland

Abstract: In recent years, clinical studies have been undertaken with

selected monoclonal antibodies (MoAbs) in the treatment of several
hematological diseases, especially in malignant disorders. However,
some clinical observations indicate that MoAbs may be an important
alternative for the conventional therapy of some autoimmune disorders.
Two MoAbs directed against CD20 antigen (rituximab, Rituxan,
Mabthera) and CD52 antigen (alemtuzumab, Campath-1H) seem to be
especially useful for this purpose. Autoimmune cytopenias have been
investigated in the last few years with positive preliminary results.
Key words: rituximab; alemtuzumab; campath-1H;
Rituximab seems to be an effective and safe agent for the treatment of autoimmune hemolytic anemia; immune
immune thrombocytopenias, autoimmune hemolytic anemia, cold thrombocytopenia; cold agglutinin disease; pure red cell
agglutinin disease and pure red cell aplasia. Although the case series are aplasia
small, rituximab seems to be an effective and safe agent for the treatment
Correspondence: Tadeusz Robak, Department
of these diseases. Clinical experience with alemtuzumab in patients with of Hematology, Medical University of Lodz, 93-513
autoimmune cytopenias is even more limited than with rituximab. Lodzd, Pabianicka 62, Poland
However, preliminary results indicate that further studies with this Tel: +4842 6895191
MoAb are warranted. A longer follow-up and the studies on larger Fax: +4842 6895192
number of patients are needed to determine the real value of these new e-mail: robaktad@onet.pl
approaches in autoimmune cytopenias. Recent experiences with the use
of MoAbs in treatment of these diseases are the subject of this review. Accepted for publication 23 October 2003

The autoimmune cytopenias (AC) include auto-
immune hemolytic anemia (AIHA), pure red cell
aplasia (PRCA), immune thrombocytopenia (ITP),
autoimmune neutropenia (AIN) and various com-
binations of these disorders, such as autoimmune
pancytopenia and EvansÕ syndrome (1). These
disorders are idiopathic or associated with other
malignant or non-malignant diseases including
lymphoma, chronic lymphocytic leukemia (CLL),
systemic lupus erythematosus (SLE), rheumatoid
arthritis, Sjogren’s disease and ulcerative colitis (2).
Despite the complex pathogenetic mechanism of
autoimmune cytopenias, B cells play a crucial role
in the pathogenesis of these disorders (3). They are
responsible for the production of autoantibodies
that are directly or indirectly (e.g. immune complex
formation) destructive. These cells also act as
highly efficient antigen presenting cells supporting
the activation and auto-reactivity of T cells
involved in the process (3). The treatment of
associated neoplastic or autoimmune diseases may
induce remission of AC in some patients. However,
in other patients specific therapy for cytopenia is
needed. The majority of patients with AC require
only standard immunosuppression, mainly steroids,
to achieve long-lasting remission. In a proportion
of refractory disease, second-line treatment such as
splenectomy, or cytotoxic drugs for ITP or AIHA
and granulocyte-colony stimulating factor (G-CSF)
for AIN is needed. However, as some patients are
resistant to conventional therapy or have significant
side effects after administration of immunosuppres-
sive agents, they need an alternative treatment.
In the last few years monoclonal antibodies
(MoAbs) directed against B and/or T cells have
become a new approach in treating patients with
severe, refractory AC, who have chronic refractory
or relapsing cytopenias and suffer life-threatening
anemia, hemorrhages or infections (1–7).
Monoclonal antibodies
The most important clinical value in the patients
with autoimmune cytopenias has human-mouse

79
Robak
antibody rituximab (Rituxan, Mabthera, F.
Hoffman-La Roche Ltd, Basel, Switzerland) that
targets CD20 antigen on B lymphocytes (5–7, 8).
Preliminary reports indicate that alemtuzumab
(Campath-1H, JLEX Pharmaceuticals, San Anto-
nio, TX, USA), a humanized rat immunoglobulin
G1 (IgG1) anti-CD52 MoAb that binds to the cell
membrane of virtually all B and T-cells is also
active in the treatment of AC (1, 4, 9, 10).
Rituximab was the first MoAb approved in 1997
by the Food and Drug Administration (FDA) for
the treatment of cancer (11). This MoAb demon-
strates significant activity in patients with various
lymphoid malignancies, including indolent and
aggressive forms of B-cell non-Hodgkin’s lym-
phoma (NHL) and B-cell CLL (8, 10). Rituximab
rapidly eliminates most circulating B cells, suggest-
ing that it could be beneficial in autoantibody-
mediated diseases by targeting the auto-reactive B
cells (11). Moreover, some studies on other auto-
immune diseases did not show any correlation
between the decline of autoantibody levels and
response, suggesting that additional mechanisms
involving antigen presentation and help to T cells
are important (7). Complement-dependent cytotox-
icity, antibody-dependent cell-mediated cytotoxi-
city (ADCC) and induction of apoptosis indicate
that rituximab is cytotoxic to CD20-positive cells.
However, CD20 is not expressed on all B-cell
forms. In particular, progenitors, as well as plasma
cells, may be devoid of CD20 and hence unrespon-
sive to this agent. Thus, after rituximab treatment
plasma cells may still continue to be present –
inducing autoantibodies for months or even years
(3). Moreover, it is unknown whether all CD20 B
cells are equally susceptible to rituximab-mediated
deletion. Until now, there is little or no data
regarding depletion of B cells at sites other than
blood. Moreover, there may be pro-survival factors
acting in certain autoimmune diseases, or in
lymphoproliferation-associated conditions, which
may protect B cells from this agent.
Rituximab is administered as an intravenous
infusion with a recommended dosage of 375 mg/
m2, once weekly for 4 wk. Treatment with this
agent is usually well tolerated. However, infusion-
related reactions occur in the majority of patients.
These adverse events are typically fever, chills,
rigors and rarely hypertension and bronchospasm,
although the incidence of these side effects
decrease with subsequent rituximab infusion.
Moreover, the prolonged impairment of antibody
production increases the risk of viral and bacterial
infections. It should also be remembered that
rituximab is a human–mouse chimeric antibody,
and hence, treated patients may be susceptible to
the development of human anti-chimeric antibod-
80
ies which can have an impact on the responsive-
ness. These host responses could attenuate
response to re-treatments and potentially mediate
allergic reactions.
Alemtuzumab is a humanized rat IgG1 anti-
CD52 MoAb that binds to the cell membrane of
virtually all normal as well as malignant lympho-
cytes, whether B cells or T cells. Similar to rituxim-
ab, alemtuzumab has the ability to cause cell lysis
using a host–effector mechanism such as comple-
ment fixation, ADCC and induction of apoptosis
(9, 10). Administration of alemtuzumab results in
prolonged and profound peripheral blood lymp-
hopenia particularly affecting T cells. Alemtuzumab
is highly active in cases of CLL are even refractory
to fludarabine, and in the T-cell variant of pro-
lymphocytic leukemia (T-PLL). The drug doses
should be increased gradually. In the first week the
first dose of 3 mg should be administered and then
increased to 10 mg and subsequently to 30 mg as
soon as infusion-related reactions are tolerated.
In CLL, alemtuzumab is usually administered
three times per week for at least 12 wk intraven-
ously or subcutaneously. This MoAb has also been
incorporated in novel conditioning regimens
designed to facilitate stem cell transplantation in
hematological malignancies. Similar to rituximab,
flu-like symptoms after the first doses of ale-
mtuzumab, especially when administered intraven-
ously, are a frequent event. More importantly this
agent induces immunosuppression which lasts for
several months after the cessation of treatment,
leading to increased susceptibility to infections. For
this reason anti-infective prophylaxis is mandatory.
Autoimmune thrombocytopenia
Autoimmune thrombocytopenia [idiopathic thrombo-
cytopenic purpura (ITP)] is an autoimmune dis-
order characterized by persistent thrombocytopenia
because of autoantibody binding to platelet anti-
gens causing their premature destruction by the
reticuloendothelial system (12). Traditionally, chro-
nic ITP is defined as persistence of a platelet count
of <150 · 109/L for more than 6 months. In
general, patients with platelet counts exceeding
30 · 109/L require no treatment unless they are
undergoing a procedure likely to induce blood loss
(13). First-line therapy comprises oral corticoster-
oids and high doses of intravenous Ig (HDIVIg).
Splenectomy is usually considered as a second-line
therapy. In patients refractory to splenectomy
having significant thrombocytopenia and hem-
orrhagic symptoms, other therapeutic modalities
including immunosuppressive agents such as vincr-
istine, azathioprine, cyclophosphamide, vinca alka-
loids, danazol, plasmapheresis, dapsone, and
 Monoclonal antibodies in autoimmune cytopenias

intravenous anti-D for Rh(D)-positive patients can

Responses only after higher doses

and responded for retreatment

be used. Those who failed to respond to standard

new response after relapse

first- and second-line therapy and who required

Two patterns of response:

In two patients R induced
Comments
treatment with monoclonal antibodies anti-CD20

Two patients relapsed

in younger patients
(rituximab) or alemtuzumab were evaluated in

early and late

Better response
several studies (14–23). The results of larger trials
are presented in Table 1.
Saleh et al. (18) reported the preliminary results
of a prospective pilot phase I/II clinical trial in
which they enrolled 13 patients with ITP who had
failed corticosteroid therapy and whose platelet

>6 m in seven patients

count was <75 · 109/L. Rituximab was adminis-

Response duration

6 m in two patients;
3 m in one patient
tered in a dose-escalating fashion using doses
ranging from 50 to 375 mg/m2, weekly for 4 wk.

60 € 480 d

21–455+ d

21–455+ d
7–56+ wk
Twelve patients completed treatment and were
evaluable for response. Rituximab-associated toxi-
city consisting of infusion-related fever and chills
was seen in less than one-third of patients and none
of the patients discontinued treatment because of

5 (20)

9 (45)

4 (57)

5 (41)

24 (31)
CR (%)

1 (8)
toxicity. None of the three patients who received
the lowest doses (50 mg/m2 followed by 150 mg/

Response
m2) achieved a clinical response. However, these
doses did not effectively deplete B cells. Three of

OR (%)

13 (52)

3 (25)

13 (65)

6 (86)

9 (75)

44 (58)
nine patients (30%) who have received rituximab at
doses close to or equal to the full dose had objective
clinical response including two complete response

R 50 to 375 mg/m2/weekly · 4
(CR) and one partial response (PR). All responding
patients have maintained their platelet count longer R 375 mg/m2/weekly · 4

R 375 mg/m2/weekly · 4

R 375 mg/m2/weekly · 4

R 375 mg/m2/weekly · 4
than 2 months without additional therapy.
Treatment
regimen

Subsequently Stasi et al. (14) presented the

results of a prospective study in 25 patients with

R, rituximab; pt, patients; d, day, wk, week; m, month; yr, year; OR, overall response; CR, complete response.
ITP treated with rituximab at a dose of 375 mg/m2
once weekly for 4 wk. The patients were resistant to
previous two–five different therapeutic options
including eight patients who had already failed
splenectomy. Five patients showed a CR (platelet
Table 1. Larger studies evaluating the efficacy of rituximab in immune thrombocytopenia

Refractory or relapsed

Refractory or relapsed
count >100 · 109/L) and a PR (platelet count
Refractory to steroids

Refractory to steroids
Refractory/relapsed
different regimens

between 50 and 100 · 109/L) was seen in another

characteristic

Refractory to 2–5
PatientsÕ

five. In additional three patients minor response

(platelet count below 50 · 1010/L), with no need for
continued treatment was observed giving an overall
response rate of 52%. In seven cases responses were
sustained for 6 months or longer. It is worth noting
that in some patients with relapsed disease repeated
46 (22–74)

40 (20–66)

challenge with rituximab induced a new response.

Age
(yr)

21–77

28–71

16–77

In responding patients a significant rise in platelet

>16

counts was observed usually 1 wk after the first

rituximab infusion. More recently, the same
authors reported the results of the treatment with
of patients
Number

rituximab in seven additional cases with ITP (16).

25

12

20

12

76

In this group the platelet count rose to >50 ·

109/L in six patients, including four patients
achieving CR and two PR. In contrast to the
Saleh et al. (18)
Stasi et al. (14)

Stasi et al. (16)

previous study, in five of the responders there was

Zaja et al. (19)

Giagounidis

no significant increase in the platelet count during

Reference

et al. (23)

rituximab treatment. Patients began to respond

Total

only 2–5 wk after last antibody administration with

81
Robak
peak platelet count occurring 10–16 wk after the
start of treatment.
Stasi et al. (14, 16) identified two patterns: early
response with an increase in platelet count after the
first or second infusion and late response with rise
of platelet count at weeks 6–8. It is possible that in
patients with early response, opsonized B cells
block the reticulo-endothelial system. In late
responders the decreased production of antiplatelet
antibodies is responsible for an increase in the
platelet count (16). However, no clear explanation
for the effect of rituximab or for the lack of
response could be found in those and other studies
(14, 16, 19, 23). In a group of 20 patients with ITP
treated with standard doses of rituximab the drug
proved to be active in 13 patients with nine
achieving CR, (19). No correlation was observed
between response and gender, time between diag-
nosis and treatment, total and CD20+ lymphocyte
count, level of CD20 expression on B cells before
the therapy and pharmacokinetics of the drug.
However, older age seems to be the factor corre-
lated with a course response rate (5).
It should be noted that rituximab is active not
only in ITP but also in secondary immunothromb-
ocytopenia in the patients with connective tissue
diseases, chronic graft vs. host disease and B-cell
lymphoproliferative disorders, including those with
purine nucleoside treatment associated ITP (19, 24–
26). Hegde and his colleagues (25) reported three
CLL patients with refractory fludarabine-associ-
ated ITP treated with standard doses of rituximab
(375 mg/m2/wk for 4 wk). The patients achieved a
platelet count of >50 · 109/L on day 21. These
results indicate that rituximab can rapidly reverse
refractory fludarabine-associated ITP. Similarly,
Hensel and Ho (27) described a case of the hairy
cell leukemia with autoimmune thrombocytopenia
after treatment with pentostatin. One week after the
first administration of rituximab, the peripheral
blood count recovered with a normal platelet
count. The mechanism by which purine nucleoside
treatment-associated cytopenias respond to the
treatment with rituximab is not clear. However,
some authors hypothesize that profound suppres-
sion of CD4 cells by fludarabine or cladribine may
cause aberrations of the immunoregulatory circuits
involving malignant B cells and on this basis it is
presumed that B-cell-mediated autoimmune com-
plications may improve by anti-CD20 therapy (25).
There is not much literature on the use of
alemtuzumab in the treatment of ITP. However,
10 yr ago Lim et al. (21) first reported the results of
treatment with this MoAb in six patients with ITP
refractory to conventional therapy. Three patients
had underlying CLL/non-Hodgkin’s lymphoma
and one had Hodgkin’s disease. Four of five
82
evaluated patients responded to the treatement. In
three patients the remission lasted more than
4–9 months. However, worsening of thrombocy-
topenia during antibody therapy was observed in
two patients and in most cases the response began
between 4 and 6 wk after the start of the antibody
therapy.
More recently Willis et al. (4) described 21
patients with severe and life-threatening autoim-
mune cytopenias resistant to standard immunosup-
pression therapies and treated with alemtuzumab.
In this group one patient had ITP, three ITP and
AIHA (EvansÕ syndrome), three ITP, AIHA and
AIN, one ITP and AIN and one ITP and PRCA.
Alemtuzumab was administered at a dose of 10 mg/
d for 10 d. A response was seen in two patients with
EvansÕ syndrome but both relapsed in 3 months. A
patient with ITP with severe hemorrhages associ-
ated with AIN had a sustained response. One
patient with ITP and PRCA responded to ITP but
relapsed 3 months later. It should be noted that
patients entering the study received cyclosporine
after alemtuzumab in an attempt to reduce the
incidence of relapse. Alemtuzumab was well toler-
ated in all patients apart from first-day reactions,
observed in most patients. Alemtuzumab is cur-
rently approved for the treatment of B-CLL resist-
ant to alkylating agents and fludarabine (10).
However, in this disease the drug is administered
at a dose of 30 mg in 2 h i.v. infusion three times
weekly for a maximum period of 12 wk. It is
possible, that the method of its administration in
ITP and other cytopenias is not optimal and better
results could be obtained with longer treatment.
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia results from the
production of pathologic antibodies that bind to
red blood cells and lead to their destruction. These
syndromes can be classified according to the
characteristic temperature activity of the antibodies
(28). The established treatment of the warm type of
AIHA consists of corticosteroids in monotherapy
or combined with azathrioprine or cyclophospha-
mide. In secondary AIHA, a search for an under-
lying factor that requires specific therapy, such as
lymphoproliferative connective tissue disease, is
indicated. In steroids refractory patients splenecto-
my may be indicated.
Rituximab appeared to have efficacy in the
treatment of AIHA, both idiopathic or associated
with B-cell chronic lymphoproliferative disorders
(Table 2) (7, 29–44). Although the case series is
small, interesting results have been observed in
idiopathic AIHA with warm autoantibodies in
children. Quartier and colleagues (29) treated five
 Monoclonal antibodies in autoimmune cytopenias

children with severe idiopathic AIHA and one child

Infections complications in two patients

and 2nd response after retreatment
with autoimmune hemolysis after stem cell
transplantation with rituximab. All patients were

Long-lasting B-cell deficiency

refractory to glucocorticosteroids and two also to

Four patients in CR of LD
Comments

Three patients relapsed

splenectomy. Four rituximab infusions were given

All patients with CLL

at a standard dose of 375 mg/m2 once per week.
Two patients received eight additional infusions at
the same dose over 14 wk. All patients remained in
complete remission 15–22 months after the start of
rituximab therapy. Moreover, corticosteroids and
immunosuppressive drugs could be stopped or their
doses markedly reduced. It is important to note, that
M 13 m (7–23+)

R, rituximab; m, months; w, week; m, month; yr, year, M, median; Ig, immunoglobulins; NR, not reported; CLL, chronic lymphocytic leukemia; LD, lymphoproliferative disorders; pt, patients.
M 8 m (3–20)
there were no infusion-related side effects and severe
Response
duration

7.3–27.6 m

infections. These results have recently been con-

3–22 m
15–22 m

firmed by Zecca and colleagues (7) in a group of 15

NR

children treated with rituximab. This is the largest

series of children with AIHA treated with this agent
6 (100)
CR (%)

reported so far. In 13 cases, warm-reactive autoan-

3 (60)

9 (24)
NR

NR
NR

tibodies of the IgG type were demonstrated by the

Response

direct antiglobulin test. In four children a concom-

itant autoimmune disease was present at the time
6 (100)

4 (100)
8 (100)
5 (100)
OR (%)

13 (87)

36 (95)

of AIHA diagnosis. All patients had previously

received two or more courses of immunosuppressive
therapy. Most of the patients were given three
infusions of rituximab. With a median follow-up of
R 375 mg/m /weekly · 4–12 w
R 375 mg/m2/weekly · 2–4 w

R 375 mg/m2/weekly · 4–6 w

15 months 13 patients responded and two did not

R 375 mg/m2/weekly · 2–5
R 375 mg/m2/weekly · 4
Treatment regimen

respond. Three patients relapsed 7, 8 and 10 months

after completion the treatment, respectively, and all
three patients were re-treated with rituximab, achiev-
2

ing remission. Four further children were treated by

Motto et al. (38). Who received four to six doses of
rituximab at a dose of 375 mg/m2. All four patients
became transfusion independent and were taken off
prednisone completely.
Refractory to steroids and/or Ig

Some recent reports indicate that rituximab

PatientsÕ characteristic

should be considered in the management of lympho-

Table 2. Larger studies evaluating efficacy of rituximab in autoimmune hemolytic anemia

Refractory to prednisone

Refractory to prednisone

and chemotherapy all

proliferative disorders (LD) with steroid refractory

Refractory to steroids

Refractory to steroids

patients with LD

AIHA (33–37). Trape and colleagues (36) reported

five cases of LD who were treated successfully with
rituximab resulting in a clinical improvement of both
the AIHA and of the LD. Two patients had large
B-cell NHL, two had B-CLL and one had B-cell
prolymphocytic leukemia (PLL). All the patients
were initially treated with chemotherapy but none of
60 (46–70) yr
age (range)
Median

0.3–14 yr

0.3–70 yr
3.5–4 yr

them achieved a stable improvement of AIHA. The

44–66 yr
7–35 m

median time from chemotherapy to rituximab

administration was 3 months. The MoAb was
administered at standard doses of 375 mg/m2/wk
of patients

for 4 wk. All patients showed a recovery from AIHA

Number

6
15

4
8
5

38

and three of them also had CR. All three patients

were alive at first CR of AIHA and LD at the time of
publication from 8 to 20 months (median 8 months).
Iannitto and colleagues (37) used rituximab as rescue
Quartier et al. (29)

Motto et al. (38)

Gupta et al. (33)
Trape et al. (36)

therapy for a patient with CLL and secondary

Zecca et al. (7)

AIHA. He was previously treated with chlorambucil

Reference

and prednisone, fludarabine, mitoxantrone, and

Total

dexamethasone, and CHOP (cyclophosphamide,

83
Robak
hydroxyrubicin, vincristine and prednisone) and
achieved only short PR after each line of therapy.
Subsequently, he was treated with rituximab at a
dose of 375 mg/m2/wk for 4 wk. The first infusion of
MoAb induced a significant reduction of lympho-
cytes and after 5 d the hemoglobin (Hb) level started
to increase. At the end of week 8 there were no signs
of AIHA with normal values of reticulocytes and
hemoglobin and only slightly positive direct anti-
globulin test (DAT) diagnosed as PR according to
NCI criteria lasting 2 months at the time of publi-
cation. Successful treatment with rituximab of ster-
oid and cyclophosphamide-resistant hemolysis in a
CLL patient was also described by Chemnitz and
colleagues (35). The patient’s condition rapidly
improved after standard doses of rituximab and the
hemolysis parameters tended to normalize on a
slightly elevated plateau. The steroid doses could be
reduced to 10 mg of prednisone per day.
Combined use of rituximab with cytotoxic agents
can be even more effective in the treatment of
AIHA in the course of CLL. Gupta and colleagues
(33) treated eight patients with steroid refractory
AIHA in patients with CLL using rituximab at a
dose 375 mg/m2 i.v. on day 1, cyclophosphamide at
a dose 750 mg/m2 on day 2 and dexamethasone at a
dose 12 mg given intravenously on days 1 and 2
and orally from day 3 to 7. Treatment cycles were
repeated at 4-wk intervals till a best response was
achieved. All eight patients achieved remission of
AIHA with a median hemoglobin level of 14.2 g/dL
following treatment and a median duration of
hemoglobin response of 13 months. The increase in
hemoglobin was evident as early as two cycles.
Moreover, five patients who were strongly Coombs
positive before treatment turned to Coombs negat-
ive. It is worth noting that five patients who
relapsed following an initial response were
re-treated with this regimen and all of them respon-
ded with long-lasting remission.
Further evidence for efficacy of rituximab in the
treatment of refractory AIHA comes from the
patients with SLE. Perotta and colleagues (43)
observed an 18-yr-old girl with SLE who developed
AIHA that did not respond to conventional treat-
ment with steroids, azathioprine and cyclosporine.
Her hemolytic disorder markedly ameliorated after
treatment with rituximab, starting a few days after
therapy and the patient remained disease-free
7 months later, at the time of writing the paper.
A patient with AIHA associated with SLE was also
among the six patients described by Quartier and
colleagues (29). This 1-yr-old child also responded
to rituximab therapy. Red blood cell transfusions
were discontinued 14 d after the start of rituximab
and normal hemoglobin concentration and reticu-
locyte counts were achieved within 4 months.
84
Autoimmune hemolytic anemia occurring after
hematopoietic stem cell transplantation is poorly
responsive to corticosteroids. The response to i.v.
Ig or splenectomy is usually also unsatisfactory.
However, recent reports of this complication with
rituximab treatment seem to be encouraging (40–
42). Hongeng and colleagues observed a case of
pediatric b-thalassemia major patients who
underwent unrelated hematopoietic stem cell trans-
plantation and developed AIHA refractory to
corticosteroids and i.v. Ig therapy (42). Subse-
quently, he received rituximab 375 mg/m2 once
weekly at a total of two doses. Hemolysis was
noted to be decreased during 3 months of obser-
vation after treatment and the corticosteroid was
tapered off and discontinued in a month after the
second infusion of MoAb. Another child with
unrelated hematopoietic stem cell transplantation
complicated by steroid refractory AIHA and
successfully treated with rituximab has been
recently presented by Corti and colleagues (40).
She received three standard doses of rituximab
and Hb reached the level of 10 g/dL 15 d after the
first dose of MoAb. Direct Coombs test positivity
progressively declined and she subsequently
become negative. Successful treatment of AIHA
complicating haplo-identical hematopoietic stem
cell transplantation was reported by Ship et al.
(41). A 7-yr-old patient received rituximab
375 mg/m2 weekly at four doses and hemoglobin
level stabilized at 11 g/dL 1 wk prior to the final
dose. He has not had a recurrence of his hemolytic
anemia 1 yr after the treatment, at the time of
publication. These three case reports indicate that
rituximab is an active agent for the treatment of
AIHA complicating hematopoietic stem cell trans-
plantation and provide a basis for future pros-
pective trials.
Experience with the use of alemtuzumab in
patients with AIHA is very limited. Willis and
colleagues (4) treated four patients with
alemtuzumab, administered at a dose of 10 mg/d
as an i.v. infusion for 10 d. Complete remission was
observed in one patient and PR in two. The
responding patients had warm-type AIHA. One
patient with cold-type AIHA had a partial response
with reduction in red cell transfusion requirements.
Unfortunately, one patient with strongly positive
DAT did not respond to treatment with
alemtuzumab and died of intractable hemolysis
and systemic venous thrombosis. These preliminary
results indicate that alemtuzumab can induce
response in severe AIHA patients who failed to
respond to conventional immunosuppression. Lar-
ger and prospective trials of this MoAb in the
treatment of AIHA who have failed first-line
therapy with steroids are desirable.
 Monoclonal antibodies in autoimmune cytopenias

improved during rituximab therapy. It is unlikely

Cold agglutinin disease
Cold agglutinin disease (CAD) is an uncommon
hemolytic anemia associated with B-cell lymphopro-
liferative disorders. This rare occurrence is related to
the production of anti-erythrocyte Ig by neoplastic
cells. Corticosteroids are of little value in treating pri-
mary CAD. Other therapeutic approaches include
alkylating agents, interferon, cladribine and splen-
ectomy, but they are also usually not effective.
Several small prospective studies and some case
reports have demonstrated the beneficial effects of
rituximab on CAD associated with the clonal
lymphoproliferation as well as idiopathic disease
(Table 3) (45–55). Among the 28 observations pub-
lished, the rate of response was 16 (89%) of which
eight (44%) achieved CR (Table 3). These results
suggest that rituximab may represent a true alter-
native to conventional immunosuppressive therapy
for the treatment of CAD. Berentsen et al. (45) in a
prospective study treated six patients with clonal
CD20+ j+ B-cell lymphoproliferations with CAD.
Three patients were previously untreated and three
pretreated with corticosteroids, chlorambucil, cyclo-
phosphamide and/or cladribine. One patient
achieved CR and three PR. Two patients failed to
show any response to rituximab despite high levels of
CD20 expression on the neoplastic cells. Similar
results, were observed by Camou and colleagues who
treated five patients with four weekly rituximab
infusions (53). The treatment a remission in all the
cases including four PR and one CR. Others single
case reports presenting successful treatment of ster-
oids and chemotherapy refractory CAD have also
been presented (46–49, 50, 54).
In some patients, rituximab was used in combination
with IFN-a (47) or corticosteroids and cyclophosph-
amide (50). However, in these patients hemolysis
Table 3. Studies evaluating efficacy of rituximab in cold agglutinin disease
that these additional agents play a role in inducing
remission of hemolysis but they may influence the
underlying lymphoproliferative diseases.
Significant improvement has also been shown in
a patient with refractory mixed cryoglobulin syn-
drome (type 2) (56) and in a patient with mixed
warm and cold AIHA not associated with lympho-
proliferative disease who relapsed after tapering of
corticosteroids (52).
These preliminary results indicate that rituximab
may represent an effective option to conventional
immunosuppressive therapy for the treatment of
CAD and other autoimmune hemolytic disorders.
However, further studies of this MoAb in patients
with this diseases are warranted.
Monoclonal antibodies in the treatment of pure red cell
aplasia
Pure red cell aplasia is a rare hematological syn-
drome that results from an isolated depletion of
erythroid precursors from the bone marrow. The
disease may present in acute or chronic form,
frequently in association with thymomas, lympho-
proliferative disorders, autoimmune diseases, treat-
ment with certain drugs and infections. Primary
PRCA is considered to result from the presence of a
soluble inhibitory factor which is localized to the Ig
fraction and targets undefined molecules on eryth-
roid cells at any stage of differentiation between
erythrocyte burst forming units (BFU-E) and eryth-
roblasts. Treatment of PRCA usually involves ster-
oids and/or immunosuppressive drugs including
cyclosporine and cyclophosphamide. However, only
about half of the patients respond to such therapy.
Recently, some case reports have suggested that
rituximab may effectively restore erythropoiesis in

Response
Number Age Patients' Response
Reference of patients (years) characteristic Treatment regimen OR (%) CR (%) duration Comments
2
Berentsen et al. (45) 6 55–80; Primary CAD, three R 375 mg/m /weekly · 4 4 (67) 1 (57) 6–14 m; One relapsed patient
mean 68 patients untreated median 11 m responded for R re-treatment
Camou et al. (53) 5 NR Primary CAD R 375 mg/m2/weekly · 4 5 (100) 1 (20) 9 and 11 m
Eneglhardt et al. (54) 2 50, 60 Refractory R 375 mg/m2/weekly · 4 2 (100) 2 (100)
Lee et al. (51) 1 75 Secondary NHL R 375 mg/m2/weekly · 4 1 1 NR Rapid and sustained response
Refractory to CY after R therapy
Layios et al. (47) 1 67 Secondary NHL R 375 mg/m2/weekly · 4 1 1 8m Patient was treated with IFN-a
Refractory simultaneously with R therapy
2
Zaja et al. (46) 1 72 Refractory to prednisone R 375 mg/m /weekly · 4 1 1 10 m
and AZ
Mori et al. (49) 1 52 Primary CAD R 375 mg/m2/weekly · 4 1 0 3+m Lymphoma cells disappeared
after R therapy
Cohen et al. (48) 1 65 Primary CAD R 375 mg/m2/weekly · 4 1 1 8+m
Total 18 50–80 16 (89) 8 (44) 3 € 14 m

CAD, cold agglutinin disease; R, rituximab; CY, cyclophosphamide; m, months; OR, overall response; CR, complete response; NHL, non-Hodkgin's lymphoma NR, not reported;
IFN-a, interferona; AZ, azathioprine.

85
Robak

Table 4. Studies evaluating rituximab in pure red cell aplasia

Reference Age Disease characteristic Previous treatment Treatment Response

Ghazal (59) 79 yr PRCA, CLL IVIG, P R 375 mg/m2/weekly · 8 CR of PRCA 10 + m

Ghazal (59) 47 yr PRCA, CLL FA R 375 mg/m2/weekly · 8 CR of PRCA 12 + m
Auner et al. (57) 68 yr Primary PRCA CS, ALG R 375 mg/m2/weekly · 3 CR of PRCA 12 + m
Zecca et al. (58) 18 m Acquired PRCA, AIHA MP, IVIG, CS R 375 mg/m2/weekly · 2 CR 5+m
Battle et al. (60) 58 yr PRCA, CLL P, Chl, CS R 375 mg/m2/weekly · 4 CR of PRCA 6+m
Total 18 m to 79 yr All refractory 100% CR

NHL, non-Hodgkin's lymphoma; PRCA, pure red cell aplasia; AIHA, autoimmune hemolytic anemia; CLL, chronic lymphocytic leukemia; CS, cyclosporine; MP, methyl
prednisolone; Chl, chlorambucil; IVIG, intravenous immunoglobulins; P, prednisone; R, rituximab; CR, complete response; FA, fludarabine; ALG, antilymphocyte globulin; yr, years;
m, months.

patients with acquired PRCA, even if immunosup-
pressive therapies have failed (57–63). The results are
summarized in Table 4. Auner and colleagues trea-
ted a 68-yr-old man with acquired PRCA refractory
to conventional treatment including prednisone,
erythropoietin and antithymocyte globulin (ATG)
with rituximab (57). Subsequently, he received
rituximab at a dose of 375 mg/m2, administered
weekly for a total of three doses. The rapid increase
in reticulocyte counts a few days after first rituximab
infusion was observed. Simultaneously, almost
complete disappearance of CD19+ B cells from
the peripheral blood was seen. Three months after
completion of therapy the reticulocyte count was
89 · 109/L and the hemoglobin had reached 12.8 g/
dL without red cell transfusion. Similar observation
was made by Zecca and colleagues who gave
rituximab only twice in an 18-month-old girl (58).
The treatment resulted in marked depletion of B cells
and rise in reticulocyte count and hemoglobin levels
leading to transfusion independence and normal
values of these parameters for 5 months without
therapy at the time of publication. This case report
suggests that lower doses of rituximab than those
needed for the treatment of lymphomas may be
highly effective in eliminating the erythropoietic
inhibitor from the patient’s serum.
Pure red cell aplasia occurs in approximately 5%
of CLL, most often in the course of disease but also
at presentation. Two recent case reports suggest
that rituximab is an effective treatment of this CLL
complication (59, 60). Ghasal observed two
patients with B-cell CLL and PRCA, one detected
during de novo presentation and one during therapy
with fludarabine (60). The first patient did not
respond to cyclosporin A, prednisone and i.v. Ig
and then responded dramatically to rituximab
administered at 375 mg/m2/wk for eight consecu-
tive wk. His reticulocyte count rose to 25% and by
the eighth week on rituximab his hemoglobin level
was 12.1 g/dL and did not need a transfusion
during 8 months follow-up. The second patient
developed PRCA after five cycles of fludarabine.
Rituximab was administered 6 wk after last cycle of
fludarabine treatment at a dose of 375 mg/m2/wk
for 8 wk and her reticulocyte count increased
gradually from 0.1% to 10% by the eighth week
of rituximab therapy. A year after the initiation of
rituximab treatment the patient’s hemoglobin and
reticulocyte count were normal. Similar results were
presented by Battle and colleagues (59). They
reported a patient with CLL in prolymphocytic
transformation who developed PRCA without
response to cyclosporin A but who responded to
rituximab therapy. MoAb was administered at
standard doses weekly for 4 wk. Six months after
rituximab therapy the patient remained well with a
stable hemoglobin level of 12.0 g/dL.
Pure red cell aplasia is also a well-recognized
complication of allogeneic hematopoietic cell trans-
plantation. Its development poses difficult thera-
peutic problems. Maschan and colleagues reported
successful treatment of PRCA with a single dose of
rituximab (200 mg/m2) in a child after major ABO-
incompatible peripheral blood allogeneic stem cell
transplantation for acquired aplastic anemia (61). It
should be noted however, that a case of PRCA
caused by chronic persistent parvovirus B19 infec-
tion in a patient treated with rituximab for non-
Hodgkin’s lymphoma has been also reported (62).
Administration of i.v. Ig is an effective treatment of
this complication.
Clinical experience with alemtuzumab in patients
with PRCA is very limited. Nevertheless, Willis and
colleagues treated four patients with PRCA with
alemtuzumab (4). Response was obtained in two
patients at 2 months and at 6 wk, respectively, and
two patients were non-responders. Recently,
another patient with PRCA coexisting with CLL
and unresponsive to corticosteroids and Ig was also
successfully treated with alemtuzumab (63).
Conclusions
The results presented above indicate that MoAbs
are highly active and well tolerated in autoimmune
cytopenias. In particular, rituximab appeared to
have significant efficacy in the treatment of refract-

86

ory or relapsed ITP, AIHA, CAD and PRCA,
refractory or relapsed after conventional immuno-
suppressive therapies. Alemtuzumab has not been
used very often in the treatment of these disorders.
However, very preliminary results in the single
centers may indicate that this drug is also poten-
tially useful in autoimmune disorders. An expand-
ing group of MoAbs directed against antigens on
the cells of immune system provides great promise
for therapeutic advances in patients with autoim-
mune cytopenias. However, it should be noted that
MoAbs are still experimental therapies in these
diseases. The majority of available data come from
retrospective, uncontrolled studies or even single
case reports. Currently prospective controlled stud-
ies are not available. In the future prospective
randomized studies, the benefit of MoAbs should
be weighed against their potential risks. In such
studies the optimal schedules of MoAbs adminis-
tration and the duration of the clinical effect should
also be evaluated.
Acknowledgements
This work was supported in part by grant from the Medical
University of Lodz, Poland no. 503–106–2 and by the Foun-
dation for the development of Diagnostics and Therapy,
Warsaw, Poland. I thank Ms Krystyna Marszalek for secre-
tariat assistance.
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